Emergence of SARS-CoV-2 through recombination and strong purifying selection

Li, Xiaojun; Giorgi, Elena E.; Marichannegowda, Manukumar Honnayakanahalli; Foley, Brian; Xiao, Chuan; Kong, Xiang‐Peng; Chen, Yue; Gnanakaran, S.; Korber, Bette; Gao, Feng

doi:10.1126/sciadv.abb9153

Cited by 368 publications

(454 citation statements)

References 48 publications

(122 reference statements)

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“…2), suggesting that the evolution of these genes is not driven by recombination. Li et al studied the origin of SARS-CoV-2 and showed evidence of strong purifying selection in the S and other genes among bat, pangolin and human coronaviruses, indicating similarly strong evolutionary constraints in different host species [40]. Likewise, our results show that purifying selection drives evolution at the whole structural gene level of SARS-CoV-2 during its transmission between human hosts (Table 2; Additional le 1: Figure S1).…”

Section: Discussionsupporting

confidence: 73%

“…High nucleotide diversity (π; Table 1) of the S gene was detected in SARS-CoV-2 isolates, suggesting that it may bene t virus survival in human hosts. Recombination has played an important evolutionary role during the emergence of SARS-CoV-2 [39,40]. It has been reported that SARS-CoV-2 is a recombinant virus of bat and pangolin (Manis javanica) CoVs, suggesting a critical role of recombination [39].…”

Section: Discussionmentioning

confidence: 99%

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Molecular Evolution of SARS-CoV-2 Structural Genes: Evidence of Positive Selection in the Spike Glycoprotein

Zhan

Zhang

Zhou

et al. 2020

Preprint

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Background: SARS-CoV-2 has caused a global pandemic since early 2020 and remains a serious public health issue worldwide. Four structural genes, envelope (E), membrane (M), nucleocapsid (N) and spike (S), play a key role in controlling entry into human cells and virion assembly of SARS-CoV-2. The evolution of these genes may determine infectivity of SARS-CoV-2, but thus far, little is known about them. Methods: We analyzed 3090 SARS-CoV-2 isolates from the GenBank database to determine the evolutionary patterns of the four structural genes by employing various molecular evolution algorithms. Results: Phylogenetic analyses showed that global SARS-CoV-2 isolates can be clustered into three to four major clades based upon protein sequence. Although intragenic recombination was not detected among different alleles, purifying selection has affected the evolution of these genes. By analyzing full genomic sequences of these alleles, our result revealed that codon 614 of the S glycoprotein has been subjected to a strong positive selection pressure, and a consistent D614G mutation was identified. Additionally, another potentially positive selection site at codon 5 in the signal sequence of the S protein was also identified with a consistent L5F mutation. The allele containing the D614G mutation has undergone significant expansion during SARS-CoV-2 transmission, implying a better adaptability of isolates with the mutation. Nevertheless, L5F allele expansion was found to be relatively restricted. The D614G mutation is located at subdomain 2 (SD2) of the C-terminal portion (CTP) of the S1 subunit. Protein structural modeling showed that the D614G mutation may cause the disruption of a salt bridge between S protein monomers and increase their flexibility, consequently promoting receptor binding domain (RBD) opening, virus attachment, and ultimately entry into host cells. Located at the signal sequence of S protein, the L5F mutation may facilitate protein folding, assembly, and secretion of the virus. Conclusions: This is the first reported evidence of positive Darwinian selection in the spike gene of SARS-CoV-2. This finding contributes to a broader understanding of the adaptive mechanisms of this virus, and provide insight for the development of novel therapeutic approaches, as well as the creation of effective vaccines, through targeting mutation sites.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Molecular Evolution of SARS-CoV-2 Structural Genes: Evidence of Positive Selection in the Spike Glycoprotein

Zhan

Zhang

Zhou

et al. 2020

Preprint

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“…Further work by others has generated a general picture of the structure of the SARS-CoV-2 genome based on breaks in homology in comparison to other known coronaviruses. As determined by Li et al (23), the vast majority of the RNA sequence of SARS-CoV-2 is derived from a relatively recent common ancestor with Bat_RaTG13. Similarity plots (SimPlot) detected a number of sudden changes in the percent similarity between SARS-CoV-2 and the base RaTG13-like sequence, accompanied by a change in similarity of RaTG13 to other viruses.…”

mentioning

confidence: 91%

“…For the purpose of my analysis, the direction of donation of the ACE2 receptor binding function is not relevant, simply that a clear area of recombination involving these otherwise closely related viruses from the same subclade has been identi ed by both Li et al (23) and Boni et al (25).…”

mentioning

confidence: 99%

A Palindromic RNA Sequence as Common Breakpoint Contributor to Copy-choice Recombination in SARS-CoV-2

Gallaher

2020

Preprint

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Much remains unknown concerning the origin of the novel pandemic Coronavirus that has raged across the globe since emerging in Wuhan of Hubei province, near the center of the People’s Republic of China in December of 2019. All current strains of Coronaviridae have arisen by a combination of incremental adaptive mutations, against the backdrop of many recombinational events throughout the past, rendering each a unique mosaic of RNA sequence from diverse sources. The consensus among virologists is that the base sequence of the novel coronavirus, designated SARS-CoV-2, was derived from a common ancestor of a bat coronavirus, represented by the strain RaTG13 isolated in Yunnan province in 2013. Into that ancestral genetic background, several recombination events have since occurred from other divergent bat-derived coronaviruses, resulting in localized discordance between the two. One such event left SARS-CoV-2 with a receptor binding domain (RBD) capable of binding the human ACE-2 receptor lacking in RaTG13, and a second event uniquely added to SARS-CoV-2 a site specific for furin, capable of efficient endoproteolytic cleavage and activation of the spike glycoprotein responsible for virus entry and cell fusion. This paper demonstrates by bioinformatic analysis that such recombinational events are facilitated by short oligonucleotide “breakpoint sequences”, similar to CAGAC, that direct recombination naturally to certain positions in the genome at the boundaries between blocks of RNA code and potentially RNA structure. This “breakpoint sequence hypothesis” provides a natural explanation for the biogenesis of SARS-CoV-2 over time and in the wild.

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“…The study further takes an unconventional approach to form an assumption that the hypothesis is true, and explores the possibility of future re-emergence (Li et al, 2020), taking into account COVID-19 infections occurring across geographical, multiethnic, multi-cultural environments, with the possible creation of multiple recombination platforms, and a large pool of SARS-CoV-2 quasispecies. Shen et al, while studying the genomic diversity of SARS-CoV-2 in the COVID-19 patients, have also emphasized on similar lines (Neher et al, 2020;Shen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Comparative Domain-Fold Analysis of the SARS-CoV-2 ORF1ab Polyprotein: Insight into Co-Evolution, Conservation of Folding Patterns, Potential Therapeutic Strategies, and the Possibility of Reemergence

Karmakar¹,

Kumar²,

Katiyar³

2020

Preprint

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The high transmissibility and replication of SARS-CoV-2 have been attributed to enhanced protein functions which are dependent on protein folding. Our in silico study endeavored to scrutinize SARS-CoV-2 ORF1ab by analyzing the conserved folding patterns of its transcribed proteins. Accordingly, the findings indicated that SARS-CoV-2 ORF1ab shares domain-specific fold-fingerprints with a spectrum of unrelated organisms. Closer observation revealed slight changes in folding patterns engendered with small variation in the intrinsic amino acid sequence. By correlating with the evolvability-potential of RNA-viruses and COVID-19 pandemic, we hypothesize that SARS-CoV-2 could undergo fast recombination with the host, SARS-CoV-2 minor variants and other viral species resulting in a reservoir of SARS-CoV-2 quasispecies. It is highly possible that natural selection will cause a future emergence of evolved SARS-CoV-2-descendants. Nonetheless, we hope that this insightful study will assist in elucidating SARS-CoV-2 protein functionalities, development of vaccines, and the possibility and nature of future emergence.

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Emergence of SARS-CoV-2 through recombination and strong purifying selection

Cited by 368 publications

References 48 publications

Molecular Evolution of SARS-CoV-2 Structural Genes: Evidence of Positive Selection in the Spike Glycoprotein

Molecular Evolution of SARS-CoV-2 Structural Genes: Evidence of Positive Selection in the Spike Glycoprotein

A Palindromic RNA Sequence as Common Breakpoint Contributor to Copy-choice Recombination in SARS-CoV-2

Comparative Domain-Fold Analysis of the SARS-CoV-2 ORF1ab Polyprotein: Insight into Co-Evolution, Conservation of Folding Patterns, Potential Therapeutic Strategies, and the Possibility of Reemergence

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